Viral infection of the central nervous system (CNS) is associated with a variety of neurologic diseases including meningitis, encephalitis, and myelitis, which have substantial morbidity and mortality and for which successful treatments are limited. The events that lead to virus-induced cell death, tissue injury and disease are not clearly understood. An increased understanding of the mechanisms by which neurotropic viruses kill cells in the CNS is thus a critical factor in the design of new therapeutic strategies. Apoptosis has been implicated as a mechanism of virus-induced CNS disease. In this proposal apoptotic signaling pathways and the regulation of these pathways will be investigated following viral infection of the CNS. Reovirus infection of neonatal mice and cultured neurons, which has proved to be one of the most important models for studying viral pathogenesis in the CNS, will be used for these studies. The role of virus-induced mitogen activated protein kinases (specific aim 1), transcription factors (specific aim 2) and gene expression changes (specific aim 3) will be investigated during death receptor and mitochondrial apoptotic signaling following reovirus infection of neuronal cells. In specific aim 3 non-targeted (microarray analysis), in addition to targeted, approaches will be used in order to elucidate novel viral mechanisms of CNS pathogenesis. Taken together these studies are designed to identify the regulation of apoptotic signaling during virus-induced apoptosis of the CNS. They are expected to have direct therapeutic implications for the development of novel therapies for CNS disease.